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When the Levee Breaks: Protein Overwhelmed by Overeating Leads to Metabolic Diseases

A nutrient gate in fat cells serves as signal router between the immune system and metabolism
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© ISTOCKPHOTO/KATI NEUDERT
A protein found in fat tissue may keep the body's immune system from treating food like a foreign invader, says a new study appearing in the May 4 issue of Cell.

The finding could help doctors determine if a person is more susceptible to developing insulin resistance, fatty liver disease, type 2 diabetes or heart disease. One day it could also lead to a treatment capable of severing the link between these illnesses and overeating or obesity.

According to the new report's senior author, Gökhan Hotamisligil, a professor of genetics and metabolism at the Harvard School of Public Health, obesity is considered a risk factor for many metabolic disorders characterized by inflammation. Inflammation is one of the ways the body responds to injury; it includes sending immune cells to eliminate tissues damaged by irritants like invading microbes. When inflammation is improperly induced, as in autoimmune disorders, it can sometimes damage healthy cells and disrupt bodily functions. In the case of diabetes, some researchers believe that inflammation in fat cells (as well as muscle and pancreatic cells) causes them to develop resistance to insulin, a hormone that regulates metabolism and is deficient in diabetics.

"[In conducting this study,] we were trying to understand if obesity leads to inflammation," Hotamisligil explains. "You're constantly bombarded with nutrients [from eating], so why, up to a certain point, do you not run into these problems?"

Hotamisligil's team began its search by performing a genome-wide screen for DNA that codes for proteins participating in both the metabolic and immune systems of mice. The proteins had to meet several criteria: they had to be activated by both systems; be present in tissues that clear nutrients from the blood, like fat tissues; have a hand in regulating inflammation; and have a body-wide metabolic effect.

Only three or four genes fit the bill. One of them codes for a protein called STAMP2, which is expressed in the fat, liver and muscle tissues of mice. (In humans, it has been found in the heart, lung, liver and prostate; human fat tissue has not yet been checked for STAMP2's presence.)

When the study authors engineered fat cells both in test tubes and in a mouse model to underproduce STAMP2, they discovered that this deprivation led to increased inflammatory and altered metabolic responses to excess nutrients. In a live mouse, the effects of STAMP2-loss included disrupted activity of insulin, development of fatty liver disease, and high blood sugar and cholesterol both when mice were fed normal diets and when they were genetically predisposed to obesity.

STAMP2's job in the body, Hotamisligil says, appears to be greeting a nutrient and routing it to the proper site for either storage or to be broken down. In addition, every time food enters the body, the immune system needs to be informed that the nutrients are not foreign invaders. "It's a very neat system that kind of keeps the gates from nutrient-flooding," he says. "In order for this to be done in an effective manner without causing inflammation, you need molecules like STAMP2. … In the obese, this cannot happen, there is some increase due to a constant flow of energy, so it can no longer do this greeting." In other words, in obese people STAMP2 functions like a levee that is overwhelmed by too much sustenance, triggering an inflammatory response.

Hotamisligil says his team discovered that STAMP2 is typically present in low levels in mouse fat cells and then, when it is activated, its levels go up and it is put to work when nutrients arrive. If the researchers can figure out how the protein knows when to activate and function, he says, "This will, first, tell us an incredibly exciting piece of information: how to signal nutrient status in molecular machinery." From there, he explains, they can probe how to strengthen this barrier and possibly find therapies to thwart the rise of chronic metabolic disorders. "These [metabolic illnesses] are not associated with necessarily severe obesity," he adds. "Small accumulation of visceral fat can trigger all these effects."

He notes, however, such a treatment option is years away. In the meantime, this research could offer the opportunity to determine who in the population are most susceptible to metabolic disease by determining the relative strength of one's gene for STAMP2.

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